Relevance: The goal of this project is to determine the role of oxidative stress in determing the ability of[unreadable] different particles to cause inflammation in the airways and why some individuals are far more susceptible to[unreadable] the adverse effects of particles than others.[unreadable] The ability of diesel exhaust particles (DEP), a major constituent of particulate matter (PM), to exacerbate[unreadable] and initiate allergic airway disease is now firmly established. While other particles can have similar effects,[unreadable] their potency can vary considerably. The central hypothesis to be tested in this study is that oxidative stress[unreadable] is the key mechanism by which DEP and ambient PM induce these pro-inflammatory effects in the human[unreadable] respiratory tract. We propose that responsiveness to PM is determined by the equilibrium between injuryprovoking[unreadable] oxidative stress and the antioxidant/anti-inflammatory effects of Phase II enzymes that normally[unreadable] protect the airways. Moreover, we propose that differences in this equilibrium can explain why some[unreadable] individuals are more susceptible to the adverse effects of PM than others. Oxidative stress in the respiratory[unreadable] tract is a natural consequence of inflammation in these diseases. A hierarchical model has been proposed in[unreadable] which at low levels of oxidative stress, an antioxidant response predominates and as the oxidative stress[unreadable] levels increase, yields to pro-inflammatory responses. We will use our established human nasal exposure[unreadable] model in already identified cohorts of high and low DEP responders to test the validity of the hierarchical[unreadable] oxidative stress model in vivo by studying these responses to PM with strong (ultrafine particles from[unreadable] ambient concentrated air), moderate (fine particles from ambient concentrated air) and weak (inert carbon[unreadable] black) intrinsic abilities to generate oxidative stress: In Aim 1 we will test the hypothesis that the intrinsic[unreadable] ability of different types of ambient PM to induce reactive oxygen species determines nasal inflammatory[unreadable] responses in humans. In Aim 2 we will test the hypothesis that the intrinsic ability of defined high and low[unreadable] responder individuals to generate antioxidant/anti-inflammatory responses determines the level of their PM[unreadable] driven nasal and peripheral blood monocyte inflammatory responses. In Aim 3, we will study the genetic[unreadable] basis for PM susceptibility in humans and test the hypothesis that gene and protein expression profiles differ[unreadable] between high vs. low DEP responders by performance of gene expression networks and proteomics.